NaV1.8 Sodium Channel Blocker Shows Promise For Acute Pain

Two phase II trials of acute pain control—one after abdominoplasty, the other after bunionectomy—reported efficacy for VX-548, an investigational selective blocker of NaV1.8 voltage-gated sodium channel on peripheral nociceptive neurons.

"The highest dose, but not lower doses, of VX-548 reduced pain over a 48-hour period," reported Scott Weiner, MD, MPH, of Brigham and Women’s Hospital in Boston, and co-authors in The New England Journal of Medicine.

"Because SPID48 is a time-weighted assessment, pain intensity differences have a greater contribution if they are associated with a longer time interval; higher SPID48 values represent greater reduction in pain," Weiner and colleagues noted.

Baseline mean NPRS scores were similar across groups (7.2 to 7.4 in the abdominoplasty trial and 6.6 to 6.9 in the bunionectomy trial).

In the abdominoplasty trial:

• A total of 303 participants (mean age, 41.5-45.4; 70-75% White; 96-100% women) were randomized 1:1:1:1 to receive one of three treatments or placebo over the 48-hour treatment period. Treatments included high-dose placebo, middle-dose placebo, and hydrocodone bitartrate 5 mg-acetaminophen 325 mg.
• The high dose of VX-548 (100-mg oral loading dose then 50-mg every 12 hours) showed a least-squares mean difference versus placebo on the SPID48 of 37.8 (95% CI, 9.2-66.4). The middle dose (60-mg loading dose then 30-mg maintenance dose every 12 hours) showed similar results to placebo.
• Descriptive secondary outcomes included the percentages of participants with 48-hour reductions in the NPRS score. By treatment, respectively, proportions reaching NPRS pain reduction of 30% were 61% for the high dose, 59% for the middle dose, 54% for hydrocodone, and 48% for placebo.

In the bunionectomy trial:

• A total of 274 participants (mean age, 47.6-50.0; 67-73% White; 76-88% women) were randomized 2:2:1:2:2 to receive one of four treatments or placebo over the 48-hour treatment period. Treatments included high-dose VX-548, middle-dose VX-548, low-dose VX-548, and hydrocodone bitartrate 5 mg-acetaminophen 325 mg.
• For the high-dose of VX-548, the least-squares mean difference versus placebo on the SPID48 was 36.8 (95% CI, 4.6-69.0). Middle-dose VX-548 and low-dose VX-548 (20-mg loading dose, then 10-mg maintenance dose every 12 hours) had results similar to placebo.
• Proportions reaching NPRS pain reduction of 30% at 48 hours were 83% with high-dose VX-548, 63% with middle-dose, 76% with low dose, and 68% with hydrocodone.

Adverse events that occurred in at least 10% of the participants in any trial group were nausea, headache, constipation, dizziness, and vomiting in the abdominoplasty trial, and nausea and headache in the bunionectomy trial.

"In the abdominoplasty trial, the incidence of most of these adverse events was similar or there was a lower incidence in the VX-548 groups than in the placebo groups, except for headache (14% in the high-dose VX-548 group versus 6% in the placebo group) and constipation (9% in the high-dose VX-548 group versus 5% in the placebo group)," the authors noted.

Three participants in the abdominoplasty trial had serious adverse events, but "none of the serious adverse events were related to VX-548, hydrocodone bitartrate-acetaminophen, or placebo, according to the site investigator; all serious adverse events resolved," Weiner and co-authors wrote. No serious adverse events were seen in the bunionectomy trial.

In an accompanying editorial, Mark Wallace, MD, of the University of California, San Diego, noted that while "the results of these two small phase II trials are promising, some concerns need to be addressed."

"It is perhaps disappointing that the effect size of this very original selective peripheral sodium channel blocker was small, and limited conclusions can be made about its effectiveness as compared with other agents because it was not directly compared with hydrocodone bitartrate–acetaminophen, which is a standard drug for the treatment of acute pain," he continued. "However, these trials represent an early foray into an exciting new class of drugs in a difficult field."

Other concerns included ibuprofen (allowed as rescue medication but data on use not presented) and a primary outcome, SPID, based on a unidimensional rating of pain (the NPRS), though for patients’ relief includes other domains, like physical functioning and sleep.

Also, for acute pain, "the best primary end point remains uncertain," Wallace observed.

"Sodium channel modulation is one of many mechanisms involved in pain transmission, and it is perhaps unlikely that modulating just one mechanism will lead to large effects on pain," he added. "At the moment, postoperative pain is still best managed by multimodal therapies, such as those that combine drugs with different mechanisms."

In a review of the science behind the study that accompanied the paper, Stephen Waxman, MD, PhD, of Yale University, explained that multiple tissue-specific sodium channel subtypes are known (e.g., NaV1.4 in skeletal muscle), and that non-selective sodium channel blockers may lead to dose-limiting side effects.

"A critical property of NaV1.8 is its ability to recover rapidly after activity: it reopens after a short interval and is thus able to drive repetitive firing," Waxman wrote. "The observation of a degree of acute postoperative pain reduction in patients receiving the highest dose of the three doses tested, together with no apparent safety signal, is a step toward a proof of concept in humans of the usefulness of subtype-selective sodium-channel blockade," he observed.

This study was funded by Vertex Pharmaceuticals.

Weiner reported relationships with Bicycle Health, Cessation Therapeutics, and Vertex.

Wallace had nothing to disclose.

Waxman reported honorarium from Vertex and fees from Third Rock Therapeutics, OliPass, Sangamo Pharma, Chromocell, Exicure, Latigo Labs, Navega Therapeutics, Envida Biopharma, Ionis, Medtronic, Alnylam, Eli Lilly, Biogen, Neurona Therapeutics, Shape Therapeutics, Glaxo SmithKline, Amgen, NxGen, Site One Therapeutics, PurduePharma, Kineta Research, TetraGenetics, and Voyager Therapeutics.

Jones J, et al "Selective inhibition of NaV1.8 with VX-548 for acute pain" N Engl J Med 2023; DOI: 10.1056/NEJMoa2209870.

Wallace MS "Trials for managing acute pain—A clinically meaningful small effect size?" N Engl J Med 2023; DOI: 10.1056/NEJMe2305480.

Waxman SG "Targeting a peripheral sodium channel to treat pain" N Engl J Med 2023; DOI: 10.1056/NEJMe2305708.